Pilot Study of Radiation-Enhanced Allogeneic Cell Therapy for Progressive Hematologic Malignancy After Allogeneic Hematopoietic Stem Cell Transplantation

NCT00984165 | Terminated Phase 2 Results FDA Drug

• 2 other identifiers: 09022409-C-0224
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

Background:

• Allogeneic hematopoietic stem cell transplantation (allotransplant) has been used to treat many kinds of cancer that develop in cells from the blood or immune system. After allotransplant, donor cells take over production of the recipient s blood and immune cells, and donor immune cells can directly attack and control tumor. However, for cancers that do not respond to allotransplant, there are no proven cures.
• A single treatment with radiation can improve the potency of immune-cell therapies. This is probably because the tumor tissue is damaged in a way that new tumor proteins are exposed, attracting immune cells to the tumor. By giving only a single dose of radiation, the immune cells that are attracted to the tumor are allowed to survive and function in their usual way, traveling throughout the body and educating other immune cells to recognize tumor, and to activate and expand in order to kill the tumor cells. Some research has shown that radiation may have a widespread effect on stimulating the immune system, educating immune cells to recognize and control tumors that have not been radiated. Objectives: \- To determine whether a single treatment of radiation will help donor immune cells control cancer after allotransplant without causing excessive side effects. Eligibility:
• Recipients: Individuals 18 years of age and older who have blood cancers that have not responded to allotransplant.
• Donors: Healthy individuals 18 years of age and older who were previous allotransplant donors for one of the study recipients. Design:
• Donors will provide additional blood immune cells, called lymphocytes, through apheresis. Apheresis involves drawing blood, separating out the lymphocytes, and returning the rest of the blood to the donor.
• Recipients will receive a single dose of radiation to the greatest amount of tumor that can be irradiated safely. Researchers will intentionally leave some tumor that will not be radiated in order to evaluate whether there is a widespread response to the treatment.
• There are two treatment arms on the study.
• Arm 1: Study participants who have donor lymphocytes available and who have not had major complications from the allotransplant will be given a dose of donor cells after they receive radiation, to provide an additional boost to the donor immune response.
• Arm 2: Study participants who cannot receive donor lymphocytes because their donor is not available, they received an allotransplant from a partially matched relative, or they have had significant complications from the allotransplant - will receive radiation without additional donor lymphocytes.
• All recipients will be followed closely for side effects and for tumor response to radiation with or without donor lymphocytes. Additional tests will be performed, including tumor biopsies, bone marrow samples, and blood draws, in order to study the immune effects of radiation and donor lymphocytes.
• A separate, control group of allotransplant recipients will not receive radiation. This group will include participants whose transplant doctors plan to use donor lymphocyte therapy alone to control cancer progression. This group will donate blood immune cells through blood draws and apheresis. These cells will be examined to study the immune effects of receiving donor lymphocytes without radiation.

Conditions

Hodgkin's Lymphoma; Non-Hodgkin's Lymphoma; Chronic Lymphocytic Leukemias; Multiple Myeloma With Plasmacytoma

Keywords

Allotransplant; Relapse; Radiation; Donor Lymphocyte Infusion; Hematologic Malignancies; Multiple Myeloma; Hodgkin Lymphoma; Non-Hodgkin Lymphoma; Chronic Lymphocytic Leukemia

Outcome Measures

Primary Outcomes (1)

• Response to Graft Versus Host Disease (GVHD) Treatment

  The following criteria is used to determine response to GVHD treatment. Complete response (CR) is complete resolution of all clinical signs and symptoms of acute GVHD. Partial response (PR) is 50% reduction in skin rash, stool volume or frequency, and/or total bilirubin. Failure to maintain adequate performance status (Karnofsky Score \>/= 70%). Non-responder (NR) \<50% reduction in skin rash, stool volume or frequency, and/or total bilirubin. Failure to maintain adequate performance status (Karnofsky Score \</= 70%). Progressive disease (PD) is further progression of signs and symptoms of acute GVHD, and/or decline in performance status after the initiation of therapy.

  Up to 100 days

Secondary Outcomes (1)

• Number of Participants With Adverse Events

  Date treatment consent signed to date off study, approximately 36 months.

Study Arms (4)

Donor Lymphocyte Infusion/Radiation

EXPERIMENTAL

Subjects will receive a unmanipulated donor lymphocyte infusion (DLI) on Day 1 after radiation (single, 8-Gy fraction to the maximum number of lesions).

Procedure: Single fraction radiation; Biological: Donor Lymphocyte Infusion (DLI)

Radiation/No Donor Lymphocyte Infusion

ACTIVE COMPARATOR

Subjects will receive radiation (single, 8-Gy fraction to the maximum number of lesions).

Procedure: Single fraction radiation

Donor Lymphocyte Infusion - Control

ACTIVE COMPARATOR

Subjects will receive a unmanipulated donor lymphocyte infusion (DLI) on Day 0.

Biological: Donor Lymphocyte Infusion (DLI)

Donor Lymphocyte Infusion - Donor

ACTIVE COMPARATOR

Healthy subjects who donated lymphocytes for infusion on a treatment Arm.

Procedure: Apheresis

Interventions

Single fraction radiation PROCEDURE

8-Gy fraction of radiation

Donor Lymphocyte Infusion/Radiation; Radiation/No Donor Lymphocyte Infusion

Donor Lymphocyte Infusion (DLI) BIOLOGICAL

Unmanipulated Donor Lymphocyte Infusion

Donor Lymphocyte Infusion - Control; Donor Lymphocyte Infusion/Radiation

Apheresis PROCEDURE

Donors will undergo a 5-liter apheresis procedure on a CS-3000 or equivalent machine.

Donor Lymphocyte Infusion - Donor

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Treatment Subjects:
• Patients must have received allotransplant (related or unrelated donor) for hematologic malignancies and have disease progression with a component of solid-phase disease. Eligible diagnoses will include any acute or chronic leukemia with a solid-phase component, Hodgkin's lymphoma, any non-Hodgkin's lymphoma, including mantle cell lymphoma, multiple myeloma. Pathology slides from patients pretransplant diagnoses will be reviewed by National Cancer Institute (NCI)/Center for Cancer Research (CCR) Department of Pathology.
• Patients must have at least two distinct sites of disease:
• At least one site must be in solid phase and amenable to irradiation, determined by Radiation Oncology evaluation.
• In addition to the target(s) of irradiation, there must be disease that is discrete from local effects of the radiation that can be evaluated for systemic response to therapy.
• Patients must have disease that has failed to respond after a minimum of four weeks to:
• Evidence of complete donor-T cell engraftment (greater than 90% chimerism) of the circulating T cells
• A trial of tapering immunosuppressive therapy, including trials that are discontinued due to development or flare of graft versus host disease (GVHD)
• Patients must be 18 - 75 years of age.
• Eastern Cooperative Oncology Group (ECOG) less than or equal to 3 (Karnofsky greater than or equal to 50%).
• Life expectancy greater than or equal to 1 month.
• Arm A
• Patients with minimal to no clinical evidence of acute GVHD (Grade 0-I) or mild- chronic GVHD (GVHD Score of no more than 1 in no more than two organ systems) while off of systemic immunosuppressive therapy.
• Available source of clinical donor lymphocyte cell product, including stem cell-mobilized product.
• Patients whose related allotransplant donor is available, eligible and enrolled on this or another National Institutes of Health (NIH)/Clinical Center (CC) protocol that permits collection of a clinical donor lymphocyte cell product, and donors are first-degree relatives with genotypic identity at 5-6/6 human leukocyte antigen (HLA) loci (HLA- A, B, and DR. Haploidentical (less than 5/6 genotypic identity) allotransplant recipients will not be eligible, due to risk of severe GVHD with donor lymphocyte infusion (DLI).

You may not qualify if:

• Treatment Subjects:
• Tumor-directed therapy within two weeks of DLI.
• Patients with rapid disease progression or aggressive tumor histology which, in the opinion of the principal investigator (PI), is likely to require urgent therapy within 60 days in order to preserve organ function or quality of life, and there is an available standard therapy to which the patient has a reasonable chance of responding.
• Progressive disease that, in the opinion of the PI, requires urgent standard therapy, e.g., threatened organ function, acceptable quality of life, etc.
• Uncontrolled GVHD, i.e., either acute GVHD Grade III or chronic-moderate/severe GVHD that has not responded to the current dose of systemic therapy or any history of steroid-refractory acute GVHD, Grade IV acute GVHD, or chronic-severe GVHD.
• Active infection that is not responding to antimicrobial therapy.
• Active psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent (as determined by Principal Investigator and/or her designee).
• Pregnant or lactating. Subjects of childbearing potential must use an effective method of contraception. The effects of the immunosuppressive medications that could be required to treat GHVD are likely to be harmful to a fetus. The effects upon breast milk are also unknown and may be harmful to an infant.
• Absolute neutrophil count of less than 500 cells/microL. At the PIs discretion, patients with marrow replacement by tumor as the probable etiology of an absolute neutrophil count of less than 500 cells/microL may be eligible for enrollment.
• In order to prevent delay of potentially stabilizing palliative therapy, the following conditions will exclude eligibility: untreated active leptomeningeal involvement with malignancy, untreated brain metastasis, and other organ-threatening diseases in which palliative treatment options with reasonable probability of efficacy (15% or higher) are available. Patients with these conditions for whom available palliative options have been tried or deemed unacceptable but who otherwise meet eligibility criteria may, at the discretion of the PI, be considered for enrollment.
• Donor Subjects:
• History of a psychiatric disorder that the PI determines might compromise compliance with transplant protocol, or that does not allow for appropriate informed consent.
• Hypertension that is not controlled by medication, history of stroke, or severe heart disease (donors with symptomatic angina will be excluded). Donors with a history of coronary artery bypass grafting or angioplasty who are symptom free will receive a cardiology evaluation and be considered on a case-by-case basis.
• History of prior malignancy. However, cancer survivors who have undergone potentially curative therapy and have had no evidence of that disease for at least 5 years may be considered for lymphocyte donation on a case-by-case basis.
• Anemia (hemoglobin (Hb) less than 11 gm/dl) or thrombocytopenia (platelets less than 100,000 per ml). However, potential donors with Hb levels less than 11 gm/dl that is due to iron deficiency will be eligible as long as the donor is initiated on iron replacement therapy and the case is individually approved by NIH Department of Transfusion Medicine (DTM).

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Wattenberg MM, Kwilas AR, Gameiro SR, Dicker AP, Hodge JW. Expanding the use of monoclonal antibody therapy of cancer by using ionising radiation to upregulate antibody targets. Br J Cancer. 2014 Mar 18;110(6):1472-80. doi: 10.1038/bjc.2014.79. Epub 2014 Feb 20.

  PMID: 24556625 BACKGROUND

• Hasumi K, Aoki Y, Wantanabe R, Mann DL. Clinical response of advanced cancer patients to cellular immunotherapy and intensity-modulated radiation therapy. Oncoimmunology. 2013 Oct 1;2(10):e26381. doi: 10.4161/onci.26381. Epub 2013 Oct 17.

  PMID: 24349874 BACKGROUND

• Schirrmacher V. Complete remission of cancer in late-stage disease by radiation and transfer of allogeneic MHC-matched immune T cells: lessons from GvL studies in animals. Cancer Immunol Immunother. 2014 Jun;63(6):535-43. doi: 10.1007/s00262-014-1530-2. Epub 2014 Mar 9.

  PMID: 24610041 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Hodgkin Disease; Lymphoma, Non-Hodgkin; Leukemia, Lymphocytic, Chronic, B-Cell; Recurrence; Hematologic Neoplasms; Multiple Myeloma

Interventions

Blood Component Removal

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Hematologic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms by Site; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders

Intervention Hierarchy (Ancestors)

Therapeutics

Results Point of Contact

• Title: Dr. Ronald E. Gress
• Organization: National Cancer Institute

gressr@dc10a.nci.nih.gov

301-496-1791

Study Officials

• Ronald E Gress, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: September 24, 2009
• First Posted: September 25, 2009
• Study Start: January 19, 2010
• Primary Completion: January 18, 2013
• Study Completion: January 31, 2013
• Last Updated: May 2, 2018
• Results First Posted: September 7, 2015

Record last verified: 2018-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)